Inhibition of NLRP3 Inflammasome Activation and Pyroptosis in Macrophages by Taraxasterol Is Associated With Its Regulation on mTOR Signaling

Abstract

Taraxasterol (TAS) is an active ingredient of Dandelion (Taraxacum mongolicum Hand. -Mazz.), a medicinal plant that has long been used in China for treatment of inflammatory disorders. But the underlying mechanism for its therapeutic effects on inflammatory disorders is not completely clear. Inflammasome activation is a critical step of innate immune response to infection and aseptic inflammation. Among the various types of inflammasome sensors that has been reported, NLR family pyrin domain containing 3 (NLRP3) is implicated in various inflammatory diseases and therefore has been most extensively studied. In this study, we aimed to explore whether TAS could influence NLPR3 inflammasome activation in macrophages. The results showed that TAS dose-dependently suppressed the activation of caspase-1 in lipopolysaccharide (LPS)-primed murine primary macrophages upon nigericin treatment, resulting in reduced mature interleukin-1β (IL-1β) release and gasdermin D (GSDMD) cleavage. TAS greatly reduced ASC speck formation upon the stimulation of nigericin or extracellular ATP. Consistent with reduced cleavage of GSDMD, nigericin-induced pyroptosis was alleviated by TAS. Interestingly, TAS time-dependently suppressed the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) and mTORC2 signaling induced by LPS priming. Like TAS, both INK-128 (inhibiting both mTORC1 and mTORC2) and rapamycin (inhibiting mTORC1 only) also inhibited NLRP3 inflammasome activation, though their effects on mTOR signaling were different. Moreover, TAS treatment alleviated mitochondrial damage by nigericin and improved mouse survival from bacterial infection, accompanied by reduced IL-1β levels in vivo. Collectively, by inhibiting the NLRP3 inflammasome activation, TAS displayed anti-inflammatory effects likely through regulation of the mTOR signaling in macrophages, highlighting a potential action mechanism for the anti-inflammatory activity of Dandelion in treating inflammation-related disorders, which warrants further clinical investigation.

NLRP3/Caspase-1-Mediated Pyroptosis of Astrocytes Induced by Antipsychotics Is Inhibited by a Histamine H1 Receptor-Selective Agonist

“…However, the mechanism by which the H1 receptor regulates NLRP3/caspase-1 signaling is unclear. A recent study reported that NLRP3 signaling and pyroptosis was inhibited by rapamycin (which binds to mammalian target of rapamycin [mTOR]) in macrophages ( Yang et al, 2021 ). Previous studies have also suggested that the NLRP3 inflammasome is activated by potassium efflux and calcium influx ( Li et al, 2021a ).…”

“…In pyroptotic signaling, NLRP3 is the most widely studied NLRP and has been reported to be related to various inflammatory diseases ( Yang et al, 2021 ; Yu et al, 2021 ). Activation of NLRP3 induces the release of IL-1β in the CNS ( Cai et al, 2021 ; Tastan et al, 2021 ), while inhibition of NLRP3 stops IL-1β production, reduces pyroptosis in the CNS, and improves cognitive function ( Cai et al, 2021 ; Tastan et al, 2021 ).…”

Autophagy Regulation on Pyroptosis: Mechanism and Medical Implication in Sepsis

“…Taraxasterol, an extract from another Chinese traditional medicine dandelion, suppresses the activation of caspase-1 in LPS-treated murine macrophages. Taraxasterol displays its anti-inflammatory effects likely through regulation of the mTOR signaling pathway [ 89 ].…”

miR-99a-5p: A Potential New Therapy for Atherosclerosis by Targeting mTOR and Then Inhibiting NLRP3 Inflammasome Activation and Promoting Macrophage Autophagy

“…Nineteen targets of miR-99a-5p were identified by using the bioinformatics prediction (Figure 4(a)). Based on previous work [23], mTOR was selected for further study. It was confirmed that the overexpression of miR-99a-5p markedly reduced mTOR mRNA level, which was a negative correlation, while the miR-99a-5p inhibitor showed the opposite trend (Figures 4(b) and 4(e)).…”

“…MTOR regulated biomass accumulation and metabolism by modulating key cellular processes (including protein synthesis and autophagy) [46,47], and dysregulation of mTOR signaling has been implicated in multiple diseases, such as AS [48,49]. Furthermore, increasing studies have found that mTOR could interact with NLRP3 inflammasome and miR-99a-5p, respectively [23,24,[50][51][52]. However, accumulating studies have indicated that the same microRNA played an essential role in the treatment of various diseases by interacting with different pathways [53].…”